Guest Editor
Integrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan-Kettering Cancer Center, New York.
The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www.mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.
In addition, the About Herbs app, Memorial Sloan-Kettering Cancer Center’s very first mobile application, was launched last fall. In the week following its release on September 21, the app was downloaded more than 6,300 times, making it #4 on the top new medical apps chart. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http://itunes.apple.com/us/app/about-herbs/id554267162?mt=8.
Overview
Throughout the history of humankind, plants have been used as medicine. Although modern pharmaceuticals replaced reliance on botanicals in the last century at least in the developed world, the use of herbs once again has risen. This increased popularity has occurred over the past 2 decades following passage of the Dietary Supplement Health and Education Act.
Patients with cancer are especially drawn to the use of herbal supplements to relieve symptoms and also as alternative “treatments” per se. Up to 40% of cancer survivors self-medicate with such products.1,2 Given that these patients also use many prescription drugs, interactions caused by polypharmacy are common and problematic.
Surge of Interest
The discovery that both grapefruit juice and St. John’s wort produced significant interactions with prescription drugs led to a surge of interest in the study of herb-drug interactions. In 2004, “Herb-drug Interaction” was introduced as a Medical Subject Headings (MeSH) term, defined as “The effect of herbs, other PLANTS, or PLANT EXTRACTS on the activity, metabolism, or toxicity of drugs.” However, fewer than 1,000 articles have been indexed under this heading since its introduction.
Although acute medical problems caused by herb-drug interactions are rare, complications and death have been reported.3 In a systematic review of 890 pairs of herb-drug interactions,4 St. John’s wort was found to cause the majority of herb-drug interactions (147), followed by ginkgo (51) and kava kava (41). Warfarin (105) was identified as the drug most frequently involved, followed by insulin (41) and aspirin (36). Among drugs used in oncology, cases involving cyclosporine (16), heparin (14), and tamoxifen (11) have been reported.
Avoiding combinations of such herbs and drugs would greatly reduce the risk of harmful effects. However, patients with cancer tend to use herbs that are promoted as alternative cures. In addition, new anticancer drugs continue to be approved for use. These factors make identification of herb-drug interactions in the cancer patient population especially challenging.
Mechanisms
To understand the precise effects of herb-drug interactions in humans, both the herb and drug need to be studied together in a clinical setting. However, few such studies have been conducted. Understanding the mechanisms may help predict interactions that result in harmful effects.
The clinical effects of herb-drug interactions depend on many factors. Studies conducted to date have focused on pharmacokinetics to determine the absorption, distribution, metabolism, and elimination of simultaneous use of herbal products and drugs. The actions of microsomal enzymes of the cytochrome P450 (CYP) family and membrane transporters such as P-glycoprotein, which play important roles in absorption and metabolism, have also been investigated. Data from such studies can help develop better drugs. Similarly, information on herbal substances has also become more readily available due to advances in screening techniques.
Laboratory studies find that many herbal constituents inhibit or induce CYP enzymes. Therefore, it is likely that they interfere with the metabolism of substrate drugs. For an anticancer drug such as lapatinib (Tykerb), which is a major CYP3A4 substrate, dose adjustment may be required when used together with an herb that is a strong CYP3A4 inducer (eg, St. John’s wort) or CYP3A4 inhibitor (eg, horse chestnut). Another example is tamoxifen, a drug that relies on CYP2D6 and CYP3A4 to be metabolized to its active form. Herbs like valerian and turmeric, which inhibit these enzymes, can therefore make tamoxifen less effective.
Furanocoumarins—compounds found in the rind of grapefruit—can irreversibly bind with CYP3A4 in the intestine. When consumed together, they have been reported to cause a sevenfold increase in the absorption of simvastatin.5 Grapefruit juice also increased the absorption of drugs like cyclosporine by 38%, tacrolimus by 110%, sunitinib (Sutent) by 11%, and oxycodone by 67%.6
Another example is hyperforin, the major constituent in St. John’s wort, which induces both cytochrome P450 and P-glycoprotein by activating the pregnane X receptor.7 Human studies show that hyperforin reduces plasma levels of irinotecan8 and imatinib (Gleevec)9 by more than 40% when used concurrently. St. John’s wort also decreases overall plasma levels of warfarin, cyclosporine, and tacrolimus.
Certain herbs can cause significant pharmacodynamic interactions when used with drugs used in cancer treatment. Examples include phytoestrogens vs hormones; “blood thinning” herbs vs anticoagulants; antioxidants vs chemotherapeutic agents; and immunostimulant herbs vs immunosuppressants.
Phytoestrogens are herbal compounds that mimic estradiol. Foods containing phytoestrogens, such as soy, have been shown to confer protective effects against breast cancer. However, genistein, an isoflavone present in soy, may stimulate the proliferation of breast tumors and interfere with the action of tamoxifen.10 Phytoestrogenic effects are also exerted by ginseng, dong quai, and red clover. They are best avoided by patients with hormone-sensitive cancers.
Chemotherapy-Herb Interactions
Several studies document interactions between chemotherapy agents and some commonly used herbs. For example, anthracyclines, platinum compounds, alkylating agents, bleomycin, and epipodophyllotoxin—all of which generate free radicals for their cytotoxic effects—interact with antioxidants.11 Therefore, herbs that exert antioxidant effects such as grape seed and pine bark extracts should be avoided by patients on chemotherapy until more is known about their safety.12
To avoid the risk of herb-drug interactions, most hospitals in the United States discourage inpatient use of herbal supplements through strict policies. Only 8% of hospitals have herbal supplements in their formularies.13 In the outpatient setting, a practitioner can minimize risk by asking patients about their dietary supplement use during consultations.
Although herbs have not been proven to treat or prevent cancers, studies indicate that some herbs, such as ginger and ginseng, are effective in relieving treatment-associated symptoms. Oncology practitioners should keep an open mind and help patients select herbs that are safe and effective, and explain the reasons for rejection when an herbal product has the potential to cause harm. If use of an herb is approved, they should monitor adverse effects by encouraging patients to report any signs and symptoms. ■
Disclosure: Drs. Yeung and Cassileth and Ms. Gubili reported no potential conflicts of interest.
References
1. Gansler T, Kaw C, Crammer C, et al: A population-based study of prevalence of complementary methods use by cancer survivors: A report from the American Cancer Society’s studies of cancer survivors. Cancer 113:1048-1057, 2008.
2. Mao JJ, Cronholm PF, Stein E, et al: Positive changes, increased spiritual importance, and complementary and alternative medicine (CAM) use among cancer survivors. Integr Cancer Ther 9:339-347, 2010.
3. Haller C, Kearney T, Bent S, et al: Dietary supplement adverse events: Report of a one-year poison center surveillance project. J Med Toxicol 4:84-92, 2008.
4. Tsai HH, Lin HW, Simon Pickard A, et al: Evaluation of documented drug interactions and contraindications associated with herbs and dietary supplements: A systematic literature review. Int J Clin Pract 66:1056-1078, 2012.
5. Lilja JJ, Kivisto KT, Neuvonen PJ: Grapefruit juice-simvastatin interaction: Effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther Nov 64:477-483, 1998.
6. Won CS, Oberlies NH, Paine MF: Influence of dietary substances on intestinal drug metabolism and transport. Curr Drug Metab 11:778-792, 2010.
7. Moore LB, Goodwin B, Jones SA, et al: St. John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci USA 97:7500-7502, 2000.
8. Mathijssen RH, Verweij J, de Bruijn P, et al: Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst 94:1247-1249, 2002.
9. Frye RF, Fitzgerald SM, Lagattuta TF, et al: Effect of St John’s wort on imatinib mesylate pharmacokinetics. Clin Pharmacol Ther Oct 76:323-329, 2004.
10. Liu B, Edgerton S, Yang X, et al: Low-dose dietary phytoestrogen abrogates tamoxifen-associated mammary tumor prevention. Cancer Res 65:879-886, 2005.
11. Weiger WA, Smith M, Boon H, et al: Advising patients who seek complementary and alternative medical therapies for cancer. Ann Intern Med 137:889-903, 2002.
12. Lawenda BD, Kelly KM, Ladas EJ, et al: Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst 100:773-783, 2008.
13. Ananth S: 2010 Complementary and Alternative Medicine Survey of Hospitals. Samueli Institute, 2011. Available at www.samueliinstitute.org. Accessed September 13, 2013.
Compiled by Barrie R. Cassileth, PhD, and Jyothi Gubili, MS, Memorial Sloan-Kettering Cancer Center. The About Herbs website is managed by K. Simon Yeung, PharmD, MBA, Lac, Memorial Sloan-Kettering Cancer Center.
